Anti-plasmodial action of de novo -designed, cationic, lysine-branched, amphipathic, helical peptides

Abstract Background A lack of vaccine and rampant drug resistance demands new anti-malarials. Methods In vitro blood stage anti-plasmodial properties of several de novo -designed, chemically synthesized, cationic, amphipathic, helical, antibiotic peptides were examined against Plasmodium falciparum...

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Bibliographic Details
Published in:Malaria Journal
Main Authors: Kaushik Naveen K, Sharma Jyotsna, Sahal Dinkar
Format: Article in Journal/Newspaper
Language:English
Published: BMC 2012
Subjects:
Anomalous egress
Anti-plasmodial peptides
De novo peptide design
Kinetics of peptide uptake
Peptide binding to DNA
Plasmodium falciparum
Arctic medicine. Tropical medicine
RC955-962
Infectious and parasitic diseases
RC109-216
Arctic
Online Access:https://doi.org/10.1186/1475-2875-11-256
https://doaj.org/article/0ee38c1613874be8b49f41205c2aae14
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Summary:Abstract Background A lack of vaccine and rampant drug resistance demands new anti-malarials. Methods In vitro blood stage anti-plasmodial properties of several de novo -designed, chemically synthesized, cationic, amphipathic, helical, antibiotic peptides were examined against Plasmodium falciparum using SYBR Green assay. Mechanistic details of anti-plasmodial action were examined by optical/fluorescence microscopy and FACS analysis. Results Unlike the monomeric decapeptides {(Ac-GXRKXHKXWA-NH 2 ) (X = F,ΔF) (Fm , ΔFm IC 50 >100 μM)}, the lysine-branched,dimeric versions showed far greater potency {IC 50 (μM) Fd 1.5 , ΔFd 1.39}. The more helical and proteolytically stable ΔFd was studied for mechanistic details. ΔFq, a K-K 2 dendrimer of ΔFm and (ΔFm) 2 a linear dimer of ΔFm showed IC 50 (μM) of 0.25 and 2.4 respectively. The healthy/infected red cell selectivity indices were >35 (ΔFd), >20 (ΔFm) 2 and 10 (ΔFq). FITC-ΔFd showed rapid and selective accumulation in parasitized red cells. Overlaying DAPI and FITC florescence suggested that ΔFd binds DNA. Trophozoites and schizonts incubated with ΔFd (2.5 μM) egressed anomalously and Band-3 immunostaining revealed them not to be associated with RBC membrane. Prematurely egressed merozoites from peptide-treated cultures were found to be invasion incompetent. Conclusion Good selectivity (>35), good resistance index (1.1) and low cytotoxicity indicate the promise of ΔFd against malaria.

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